This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: In patients with Familial ALS, pyrimethamine will reduce SOD1 levels in lymphocytes and cerebrospinal fluid at doses of 100 mg of less. Amyotrophic lateral sclerosis (ALS) unfortunately remains a uniformly fatal neurodegenerative disorder for which no effective therapy exists. The clinical course of the familial form (FALS) may be particularly aggressive. Since the gene mutation is known for some forms of FALS [i.e. mutations in the gene coding for the enzyme superoxide dismutase (SOD1)], drugs which cause inhibition of gene transcription or translation would be potential potent therapeutic agents. Until now small molecules targeting this mutation or its protein expression have not been identified. Several small molecules have been identified that reduce SOD1 protein levels through various mechanisms. One candidate, pyrimethamine, is FDA approved for other indications, and has been on the market for many years. Pyrimethamine dramatically reduces SOD1 levels in mice and cells. The study's primary objective is to evaluate the safety and tolerability of pyrimethamine in patients with FALS. Secondary objectives will be to determine dose optimization for maximal SOD1 level reduction. Patients will be asked to undergo SOD1 level determination in lymphocytes and cerebrospinal fluid.